Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway
| Autor: | Jesper Gromada, Qing Yang, Mary D. L. Chau, Jiaping Gao, Zhidan Wu |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty FGF21 Adipose Tissue White Mice Obese Mitochondrion AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Mice Random Allocation Oxygen Consumption AMP-activated protein kinase Sirtuin 1 Internal medicine medicine Adipocytes Citrate synthase Animals Homeostasis Obesity Phosphorylation Protein kinase A Multidisciplinary biology AMPK Biological Sciences NAD Mitochondria Fibroblast Growth Factors Endocrinology Glucose Genes biology.protein Energy Metabolism Oxidation-Reduction Protein Kinases Signal Transduction |
| Popis: | Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD + levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK–SIRT1–PGC1α–dependent mechanism in adipocytes. |
| Databáze: | OpenAIRE |
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